14-3-3 proteins are a group of highly conserved proteins that are involved in many vital cellular processes such as metabolism, protein trafficking, signal transduction, apoptosis and cell cycle regulation. 14-3-3 proteins are phospho-serine/phospho-threonine binding proteins that have a diverse array of partners including transcription factors, biosynthetic enzymes, cytoskeletal proteins, signaling molecules, apoptosis factors and tumor suppressors. The 14-3-3 family consists of 7 isoforms; beta, gamma, epsilon, sigma, zeta, tau and eta. 14-3-3 proteins are ubiquitously expressed and self-assemble into homo- and heterodimers, with the exception of 14-3-3 sigma, which exclusively forms homodimers and is found in cells of epithelial origin only. Each monomer contains an independent ligand-binding site, thus the 14-3-3 dimer can interact with two target proteins simultaneously. 14-3-3 proteins are highly rigid structures and ligand binding can induce conformational changes that alter the stability and/or catalytic activity of the ligand. Furthermore, 14-3-3 protein binding can physically occlude sequence-specific or structural motifs on the target that prevent molecular interactions and/or modulate the accessibility of a target protein to modifying enzymes such as kinases, phosphatases and proteases. In addition, 14-3-3 proteins can act as a scaffold molecule to anchor target proteins within close proximity of one another. 14-3-3 proteins represent an integration point for proliferative, survival, apoptotic and stress signalling pathways. Members of the 14-3-3 protein family enhance the activity of many proteins with proliferative and/or survival functions, such as Raf kinases, and antagonize the activity of proteins that promote cell death and senescence, such as Bad, Bim and Bax. Because many 14-3-3 interactions are phosphorylation dependent, 14-3-3 proteins have been integrated into the core regulatory pathways that are crucial for normal growth and development. 14-3-3 proteins are directly involved in cellular processes such as cytokinesis, cell-contact inhibition, anchorage-independent growth and cell adhesion, and it is these pathways that often become dysregulated in disease states such as cancer.
Exposure of tumor cells to ionizing radiation (IR) is widely known to induce a number of cellular changes. One way that IR can affect tumor cells is through the development of neoantigens which are new molecules that tumor cells express at the cell membrane following some insult or change to the cell. There have been numerous reports in the literature of changes in both tumor and tumor vasculature cell surface molecule expression following treatment with IR. The usefulness of neoantigens for imaging and therapeutic applications lies in the fact that they are differentially expressed on the surface of irradiated tumor cells to a greater extent than on normal tissues. This differential expression provides a mechanism by which tumor cells can be “marked” by radiation for further targeting. Drug delivery vehicles or imaging agents conjugated to ligands that recognize and interact with the neoantigens can help to improve tumor-specific targeting and reduce systemic toxicity with cancer drugs.